Islet Transplantation in Type 1 Diabetic Patients Using the University of Illinois at Chicago (UIC) Protocol
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| ClinicalTrials.gov Identifier: NCT00679042 |
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Recruitment Status :
Active, not recruiting
First Posted : May 16, 2008
Results First Posted : April 6, 2021
Last Update Posted : August 30, 2023
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| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Type 1 Diabetes Mellitus | Biological: Islets of Langerhans transplantation | Phase 3 |
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This study is a Phase 3 single center, uncontrolled trial in which 1-3 allogeneic pancreatic islet transplants are performed for each study subject. Follow-up evaluations after transplant continue for 52 weeks after the final islet transplantation. Thereafter, subjects may enroll for a 5-year follow-up study and an additional 5 year to 10 year follow-up study to evaluate the function of the islets and to measure and regulate immunosuppressive drug levels and side effects.
The safety of islet transplantation depends primarily on the incidence of serious and unexpected complications or adverse events and the ability of the cell isolation laboratory to produce uncontaminated islet cell preparations with minimal endotoxin content.
All study subjects are followed for safety for one year. An independent Data Monitoring Committee (DMC), composed of 3 members who have training in medicine and/or organ transplantation, will review eligibility and safety data within 2 weeks after each islet transplantation and every two months thereafter. An independent monitor, who is knowledgeable about Good Clinical Practice (GCP) guidelines and regulations, monitors the study for compliance with 21 CFR and according to ICH GCP Guidelines. Within the Clinical Research Center, representatives of the Scientific Advisory Committee and the Research Subject Advocacy Program monitor safety. These entities report to the UIC Institutional Review Board (IRB), which also reviews safety data annually and on occurrence of serious adverse events. The principal investigator also reports serious adverse events to the US Food and Drug Administration (FDA).
Success: Islet transplantation is considered a success when subjects do not use insulin, and they achieve a fasting glucose level not exceeding 140 mg/dL more than three times in a week, and not exceeding two-hour post-prandial values of 180 mg/dL more than four times in a week.
Partial Success: Subjects who have a reduction in insulin requirements but who do not achieve insulin independence and present with a reduction in HbA1c and number of hypoglycemic episodes are considered to have partial success of islet transplantation. Reduction in insulin-requirements are assessed by comparing the pre-transplant insulin requirement recorded over two consecutive days (expressed as insulin units per kg) with the requirement on the two consecutive days preceding the subsequent islet infusion, and the requirements on two consecutive days at six months and again on two consecutive days at one year after the final transplant.
Failure: Absence of measurable levels of C-peptide after transplantation is considered as failure of islet cell transplantation.
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 21 participants |
| Allocation: | N/A |
| Intervention Model: | Single Group Assignment |
| Masking: | None (Open Label) |
| Primary Purpose: | Treatment |
| Official Title: | Islet Transplantation in Type 1 Diabetic Patients Using the UIC Protocol, Phase 3 |
| Actual Study Start Date : | September 5, 2007 |
| Actual Primary Completion Date : | July 19, 2017 |
| Estimated Study Completion Date : | June 14, 2026 |
| Arm | Intervention/treatment |
|---|---|
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Experimental: Treatment
All subjects will receive up to 3 transplantations of allogeneic human islets of Langerhans.
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Biological: Islets of Langerhans transplantation
Each subject may receive 1-3 transplantations of allogeneic human islets of Langerhans and the following medications: Basiliximab 20 mg iv 2 hours before transplant and 20 mg iv 2 weeks post-transplant; Tacrolimus 1 mg p.o. bid adjusted to reach target trough levels of 3-6 ng/ml; Sirolimus 0.2 mg/kg loading dose, then 0.1 mg/kg p.o. daily adjusted to reach target trough levels of 10-15 ng/ml during the first 3 months post transplant and 7-10 ng/ml thereafter; Etanercept 50 mg iv 1 hour before transplant and 25 mg s.c. on days 3, 7,and 10 post-transplant; Exenatide 5-mcg s.c. bid for 1 week, then 10 mcg bid for 6 months after each transplant Other Names:
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- Treatment Emergent Adverse Events [ Time Frame: From first islet transplant through one year after last transplant (maximum 3 infusions possible), an average of 1 year ]Safety endpoints: Incidence and severity of events related to islet infusion, immunosuppression, and islet preparations
- Number of Subjects Reaching the Efficacy Goal [ Time Frame: One year after islet transplant ]
A successful primary endpoint was defined as HbA1c ≤ 6.5% at the one-year follow-up visit and absence of severe hypoglycemic events (SHE) from Day 28 post-first transplant to 1 year after first and last transplant.
The primary analysis was to estimate the true rate of the composite favorable outcome at 1 year following first and last transplant in patients in the ITT population.
- Number of Patients Presenting With Insulin Independence at Day 365 Post First and Last Transplant [ Time Frame: 1 year after islet infusion ]
Number of patients presenting with insulin independence, including:
Absence of exogenous insulin injection reported at Day 365.
- Fasting capillary glucose level not exceeding 140 mg/dL (7.8 mmol/L) more than 3 times in a week (based on measuring capillary glucose levels a minimum of 7 times in a 7-day period) at Day 365 ± 28 days.
- Fasting plasma glucose level ≤ 126 mg/dL (7.0 mmol/L) at Day 365 ± 28 days (if the fasting plasma glucose level is > 126 mg/dL [7.0 mmol/L], it must have been confirmed in an additional 1 out of 2 measurements).
- Two-hour post-prandial capillary glucose not exceeding 180 mg/dL (10.0 mmol/L) more than 1 out of every 7 times in a week (based on measuring capillary glucose levels a minimum of 7 times in a 7-day period) at Day 365 ± 28 days.
- Evidence of endogenous insulin production defined as fasting or stimulated C-peptide levels ≥ 0.5 ng/mL (0.16 nmol/L) at Day 365 ± 28 days
- Hypoglycemic Episodes by HYPO Score [ Time Frame: One year after the last transplant ]
Hypoglycemic episodes will be measured by the Ryan hypoglycemic (HYPO) Score derived from the number and severity of hypoglycemic episodes recorded throughout the follow-up phase from Day 28 to Day 365.
(From Ryan et al., 2004) "A HYPO score was generated based on a combination of scores from the 4 weeks of readings and the patients' self-reported episodes over the previous year using the scoring system found in online appendix 2 (available at http://diabetes.diabetesjournals.org). The record sheets returned by the patients were analyzed for the number of episodes of glucose values recorded as <2.5 mmol/l and between 2.5 and 2.9 mmol/l. Points were awarded if symptoms were absent or were neuroglycopenic rather than autonomic... Thus the more severe the problem with hypoglycemia, the higher the score." A Ryan score ranges from 0 (no event) to a cumulative sum of episode points of total events reported during the 4 weeks then multiplied by 13 to provide a 1-year value.
- Reduction in Hypoglycemic Severity Measured by %Reduction in HYPO Score [ Time Frame: One year after the first and last transplant ]%reduction in Ryan HYPO Score [%(baseline score - 1-year post transplant score)/baseline] at time of evaluation.
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| Ages Eligible for Study: | 18 Years to 75 Years (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
Inclusion Criteria:
- Type 1 diabetes mellitus for more than 5 years complicated by the following situations that persist despite intensive insulin management efforts:
- At least one episode of severe hypoglycemia in the past 3 years defined as an event with symptoms compatible with hypoglycemia in which the subject required the assistance of another person, and which was associated with either a blood glucose level <50 mg/dL (2.8 mmol/L) or prompt recovery after oral carbohydrate, intravenous glucose, or glucagon administration
- Reduced awareness of hypoglycemia, defined by the absence of adequate autonomic symptoms at capillary glucose levels of <54 mg/dL (3 mmol/l) as reported by the subject
Exclusion Criteria:
- Co-existing cardiac disease: myocardial infarction within the past 6 months, angiographic evidence of non-correctable coronary artery disease, ischemia on functional cardiac exam, heart failure
- Active alcohol or substance abuse, including cigarette smoking (must be abstinent for six months)
- Psychiatric disorder: schizophrenia, bipolar disorder, or major depression that is unstable on medication
- History of non-adherence to prescribed regimens
- Active infection including hepatitis C, hepatitis B, HIV
- TB by history, current infection, or under treatment for suspected TB
- History of malignancies except squamous or basal skin cancer
- Family history of MEN2 or MCT
- Stroke within the past 6 months
- BMI >27 kg/m2
- C-peptide response to glucagon stimulation, any C-peptide >0.3 ng/mL
- Inability to provide informed consent
- Age less than 18 or greater than 75 years
- Creatinine clearance <80 mL/min/1.73 m2 by 24-hour urine collection
- Serum creatinine consistently >1.5 mg/dL
- Macroalbuminuria >300 mg/24h
- Baseline Hb <12 gm/dL in women, <13 gm/dL in men
- Baseline liver function tests outside normal range
- Untreated proliferative retinopathy
- Positive pregnancy test, intent for pregnancy, male's intent to procreate, unwilling to use effective contraception, breast feeding
- Previous transplant or PRA reactivity >80%
- Insulin requirement >0.7 IU/kg/day
- HbA1c >12%
- Hyperlipidemia (fasting cholesterol >130 mg/dL or fasting triglycerides >200 mg/dL
- Medical condition requiring chronic use of steroids
- Use of Coumadin or other antiplatelet or anticoagulant therapy, or PT-INR >1.5
- Factor V deficiency
- Smoking tobacco
- Addison's disease
- Allergy to radiographic contrast material
- Symptomatic cholecystolithiasis
- Acute or chronic pancreatitis
- Symptomatic peptic ulcer disease
- Severe unremitting diarrhea, vomiting, or other gastrointestinal disorders that could interfere with medication absorption
- Treatment with antidiabetic medication other than insulin within 4 weeks of enrollment
- Use of any study medication within 4 weeks of enrollment
- Received live attenuated vaccine(s) within 2 months of enrollment
- Any medical condition that, in the opinion of the investigator, might interfere with safe participation
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00679042
| United States, Illinois | |
| University of Illinois at Chicago Medical Center | |
| Chicago, Illinois, United States, 60612 | |
| Principal Investigator: | Jose Oberholzer, MD | University of Illinois at Chicago |
Documents provided by Jose Oberholzer, University of Illinois at Chicago:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
| Responsible Party: | Jose Oberholzer, Adjunct Professor of Surgery, University of Illinois at Chicago |
| ClinicalTrials.gov Identifier: | NCT00679042 |
| Other Study ID Numbers: |
IND11807-2007-0330 |
| First Posted: | May 16, 2008 Key Record Dates |
| Results First Posted: | April 6, 2021 |
| Last Update Posted: | August 30, 2023 |
| Last Verified: | August 2023 |
| Individual Participant Data (IPD) Sharing Statement: | |
| Plan to Share IPD: | No |
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Diabetes Mellitus Type 1 Type 1 Diabetes Mellitus Islets of Langerhans Transplantation Allogeneic Islet transplantation |
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Diabetes Mellitus Diabetes Mellitus, Type 1 Glucose Metabolism Disorders Metabolic Diseases Endocrine System Diseases Autoimmune Diseases Immune System Diseases Exenatide Sirolimus Etanercept Tacrolimus Basiliximab Immunosuppressive Agents Immunologic Factors Physiological Effects of Drugs |
Calcineurin Inhibitors Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action Anti-Bacterial Agents Anti-Infective Agents Antibiotics, Antineoplastic Antineoplastic Agents Antifungal Agents Anti-Inflammatory Agents, Non-Steroidal Analgesics, Non-Narcotic Analgesics Sensory System Agents Peripheral Nervous System Agents Anti-Inflammatory Agents Antirheumatic Agents |